Colorectal Cancer

Abstract

Until recently, colorectal cancer has been treated as a single disease entity with treatment decisions predominately based on patient and clinician preference as opposed to any real biological confidence in identifying which agents or strategies will probably be most effective. Therapeutic strategies have not kept up with our knowledge of the biology of the disease. This special issue aims to address developments in molecular targeting, imaging and therapeutic decision making in this disease.It is now well recognised that although 85% of colorectal cancer develops classically via chromosomal instability according to the adenoma carcinoma sequence [[1]Kinzler K.W. Vogelstein B. Colorectal tumors.in: Vogelstein B. Kinzler K.W. The genetic basis of human cancer. 2nd ed. McGraw-Hill, New York2002: 583-612Google Scholar], 15–20% occurs more rapidly through an inability to repair very short mismatches of DNA. The only molecular stratification to date in widespread practice has been the avoidance of adjuvant chemotherapy in Microsatellite unstable (MSI high) stage II cases [[2]O'Leary B. Gilbert D.C. Mismatch repair as a prognostic marker for adjuvant therapy in colorectal cancer – how soon is now?.Clin Oncol (R Coll Radiol). 2013; 25: 625-629Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] and of epidermal growth factor receptor targeted agents in RAS/RAF mutated tumours [[3]De Roock W. Piessevaux H. De Schutter J. et al.KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.Ann Oncol. 2008; 19: 508-515Crossref PubMed Scopus (738) Google Scholar]. However, a deeper understanding of the differing routes of tumourigenesis, as outlined by Biswas et al. [[4]Biswas S. Holyoake D. Maughan T. Molecular taxonomy and tumourigenesis of colorectal cancer.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar], is beginning to reveal insights that should have therapeutic implications and represent a real hope of clinically meaningful improvements in standards of care. In parallel with these advances in understanding runs the ongoing FOCUS4 trial, a multi-arm, multi-stage platform testing novel agents in biomarker stratified arms as maintenance therapy after initial chemotherapy in the metastatic setting. One important feature of this platform is the ability to adapt to new discoveries (such as the apparent sensitivity of microsatellite unstable colorectal cancer to immune checkpoint inhibition [[5]Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (5850) Google Scholar]).As a molecular understanding begins to guide treatment decisions, so too must advanced imaging techniques. This is of particular relevance in the multimodality treatment of rectal cancer [[6]Prezzi D. Goh V. Rectal cancer magnetic resonance imaging: imaging beyond morphology.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar]. The value of magnetic resonance imaging in accurately staging rectal cancers preoperatively has led to real improvements in outcome nationally, namely in reducing rates of positive resection margins and subsequent local recurrences, and is a cornerstone of multidisciplinary team working. Prezzi and Goh [[6]Prezzi D. Goh V. Rectal cancer magnetic resonance imaging: imaging beyond morphology.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] describe how dynamic techniques may better predict response to treatment and subsequent toxicities.Longstanding practical debates are covered too. Introduction of intensity-modulated radiotherapy protocols for rectal cancer has lagged behind other areas [[7]Muirhead R. Adams R.A. Gilbert D.C. et al.Anal cancer: developing an intensity-modulated radiotherapy solution for ACT2 fractionation.Clin Oncol (R Coll Radiol). 2014; 26: 720-721Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] but in this special issue, Teoh and Muirhead [[8]Teoh S. Muirhead R. Rectal radiotherapy – intensity modulated radiotherapy delivery, delineation and doses.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] review the relevant data that currently exist and suggest pointers for the future. Surgery, of course, retains primary importance in the multimodality treatment of rectal cancer and Renehan [[9]Renehan A.G. Techniques and outcome of surgery for locally advanced and local recurrent rectal cancer.Clin Oncol (R Coll Radiol). 2016; Google Scholar] provides a comprehensive overview of current techniques and areas for further development.Given the general improvements in locoregional outcomes in the management of rectal cancer, overall survival outcomes become the primary concern. The use of preoperative chemoradiotherapy poses two questions. First, can we improve on concurrent treatment with a fluoroxypyrimidine. Greenhalgh et al. [[10]Greenhalgh T.A. Dearman C. Sharma R.A. Combination of novel agents with radiotherapy to treat rectal cancer.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] review where we are with current data and discuss future approaches in terms of novel agents to combine with chemoradiotherapy. Second, Boustani et al. [[11]Boustani J. Caubet M. Bosset J.-F. Adjuvant chemotherapy in rectal cancer after chemoradiotherapy.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] address the frequent clinical question around whether to follow the operation with further adjuvant chemotherapy, showing why this is not supported by current evidence, but suggesting future studies.Undaunted by the lack of efficacy seen in the adjuvant setting, and in keeping with the shift to the neoadjuvant approach favoured in all gastrointestinal cancers (MAGIC), Gollins and Sebag-Montefiore [[12]Gollins S. Sebag-Montefiore D. Neoadjuvant treatment strategies for locally advanced rectal cancer.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] set out the case for prioritising testing further neoadjuvant chemotherapy schedules.At the other end of the spectrum are the patients who experience an apparent complete clinical response in their rectal cancer after chemoradiotherapy. Naturally, organ preservation is an attractive option (comparing the situation in anal cancer where chemoradiotherapy has replaced surgery for all but the most superficial lesions as first-line standard of care). In the case of rectal cancer, however, this remains a divisive and emotive subject, with proponents seeking to ever improve rates of complete response and treat ever earlier cancers. Yet the optimal surveillance pathways and predictors of success in this approach remain controversial. In this regard we include a balanced review of the evidence thus far and where we might go next as a clinical community [[13]Glynne-Jones R. Hughes R. Complete response after chemoradiotherapy in rectal cancer (watch and wait): have we cracked the code?.Clin Oncol (R Coll Radiol). 2015; Google Scholar].We hope you find that this collection of articles addresses current questions that weekly vex our multidisciplinary teams and gives insights into future directions. Until recently, colorectal cancer has been treated as a single disease entity with treatment decisions predominately based on patient and clinician preference as opposed to any real biological confidence in identifying which agents or strategies will probably be most effective. Therapeutic strategies have not kept up with our knowledge of the biology of the disease. This special issue aims to address developments in molecular targeting, imaging and therapeutic decision making in this disease. It is now well recognised that although 85% of colorectal cancer develops classically via chromosomal instability according to the adenoma carcinoma sequence [[1]Kinzler K.W. Vogelstein B. Colorectal tumors.in: Vogelstein B. Kinzler K.W. The genetic basis of human cancer. 2nd ed. McGraw-Hill, New York2002: 583-612Google Scholar], 15–20% occurs more rapidly through an inability to repair very short mismatches of DNA. The only molecular stratification to date in widespread practice has been the avoidance of adjuvant chemotherapy in Microsatellite unstable (MSI high) stage II cases [[2]O'Leary B. Gilbert D.C. Mismatch repair as a prognostic marker for adjuvant therapy in colorectal cancer – how soon is now?.Clin Oncol (R Coll Radiol). 2013; 25: 625-629Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar] and of epidermal growth factor receptor targeted agents in RAS/RAF mutated tumours [[3]De Roock W. Piessevaux H. De Schutter J. et al.KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.Ann Oncol. 2008; 19: 508-515Crossref PubMed Scopus (738) Google Scholar]. However, a deeper understanding of the differing routes of tumourigenesis, as outlined by Biswas et al. [[4]Biswas S. Holyoake D. Maughan T. Molecular taxonomy and tumourigenesis of colorectal cancer.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar], is beginning to reveal insights that should have therapeutic implications and represent a real hope of clinically meaningful improvements in standards of care. In parallel with these advances in understanding runs the ongoing FOCUS4 trial, a multi-arm, multi-stage platform testing novel agents in biomarker stratified arms as maintenance therapy after initial chemotherapy in the metastatic setting. One important feature of this platform is the ability to adapt to new discoveries (such as the apparent sensitivity of microsatellite unstable colorectal cancer to immune checkpoint inhibition [[5]Le D.T. Uram J.N. Wang H. et al.PD-1 blockade in tumors with mismatch-repair deficiency.N Engl J Med. 2015; 372: 2509-2520Crossref PubMed Scopus (5850) Google Scholar]). As a molecular understanding begins to guide treatment decisions, so too must advanced imaging techniques. This is of particular relevance in the multimodality treatment of rectal cancer [[6]Prezzi D. Goh V. Rectal cancer magnetic resonance imaging: imaging beyond morphology.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar]. The value of magnetic resonance imaging in accurately staging rectal cancers preoperatively has led to real improvements in outcome nationally, namely in reducing rates of positive resection margins and subsequent local recurrences, and is a cornerstone of multidisciplinary team working. Prezzi and Goh [[6]Prezzi D. Goh V. Rectal cancer magnetic resonance imaging: imaging beyond morphology.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] describe how dynamic techniques may better predict response to treatment and subsequent toxicities. Longstanding practical debates are covered too. Introduction of intensity-modulated radiotherapy protocols for rectal cancer has lagged behind other areas [[7]Muirhead R. Adams R.A. Gilbert D.C. et al.Anal cancer: developing an intensity-modulated radiotherapy solution for ACT2 fractionation.Clin Oncol (R Coll Radiol). 2014; 26: 720-721Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] but in this special issue, Teoh and Muirhead [[8]Teoh S. Muirhead R. Rectal radiotherapy – intensity modulated radiotherapy delivery, delineation and doses.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] review the relevant data that currently exist and suggest pointers for the future. Surgery, of course, retains primary importance in the multimodality treatment of rectal cancer and Renehan [[9]Renehan A.G. Techniques and outcome of surgery for locally advanced and local recurrent rectal cancer.Clin Oncol (R Coll Radiol). 2016; Google Scholar] provides a comprehensive overview of current techniques and areas for further development. Given the general improvements in locoregional outcomes in the management of rectal cancer, overall survival outcomes become the primary concern. The use of preoperative chemoradiotherapy poses two questions. First, can we improve on concurrent treatment with a fluoroxypyrimidine. Greenhalgh et al. [[10]Greenhalgh T.A. Dearman C. Sharma R.A. Combination of novel agents with radiotherapy to treat rectal cancer.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] review where we are with current data and discuss future approaches in terms of novel agents to combine with chemoradiotherapy. Second, Boustani et al. [[11]Boustani J. Caubet M. Bosset J.-F. Adjuvant chemotherapy in rectal cancer after chemoradiotherapy.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] address the frequent clinical question around whether to follow the operation with further adjuvant chemotherapy, showing why this is not supported by current evidence, but suggesting future studies. Undaunted by the lack of efficacy seen in the adjuvant setting, and in keeping with the shift to the neoadjuvant approach favoured in all gastrointestinal cancers (MAGIC), Gollins and Sebag-Montefiore [[12]Gollins S. Sebag-Montefiore D. Neoadjuvant treatment strategies for locally advanced rectal cancer.Clin Oncol (R Coll Radiol). 2016; PubMed Google Scholar] set out the case for prioritising testing further neoadjuvant chemotherapy schedules. At the other end of the spectrum are the patients who experience an apparent complete clinical response in their rectal cancer after chemoradiotherapy. Naturally, organ preservation is an attractive option (comparing the situation in anal cancer where chemoradiotherapy has replaced surgery for all but the most superficial lesions as first-line standard of care). In the case of rectal cancer, however, this remains a divisive and emotive subject, with proponents seeking to ever improve rates of complete response and treat ever earlier cancers. Yet the optimal surveillance pathways and predictors of success in this approach remain controversial. In this regard we include a balanced review of the evidence thus far and where we might go next as a clinical community [[13]Glynne-Jones R. Hughes R. Complete response after chemoradiotherapy in rectal cancer (watch and wait): have we cracked the code?.Clin Oncol (R Coll Radiol). 2015; Google Scholar]. We hope you find that this collection of articles addresses current questions that weekly vex our multidisciplinary teams and gives insights into future directions.